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Herpesvirus infections may have a pathogenic link to Alzheimer’s disease

Publish date: June 21, 2018

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Does herpesvirus join the list of infective degenerative brain diseases?

The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.

The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.

Dr. Richard J. Caselli

Second is the concept of a brain microbiome that when disrupted by certain immunosuppressive agents can give rise to progressive multifocal leukoencephalopathy (PML). Viruses live in our brain, normally under control, until something tips the scales in their favor. The time course of both CJD and PML is relatively rapid with few people surviving more than a year, and very unlike the far more slowly progressive course of Alzheimer’s disease whose symptomatic stage can last over a decade and whose preclinical stage may be more than 20 years, according to some studies. The topography of early-stage Alzheimer’s disease bears a striking resemblance to another herpesvirus that the authors did not identify, herpes simplex virus 1, which is the most common cause of viral encephalitis and is limbotropic, targeting the medial temporal lobe and adjacent structures very much like Alzheimer’s disease. Yet evidence relating HSV1 to Alzheimer’s disease has not been conclusive.

The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.

Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.

FROM NEURON

causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation .

“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”

The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.

Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.

“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”

A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.

HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.

“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”

They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).

Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.

Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.

Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across

Herpesvirus infections may have a pathogenic link to Alzheimer’s disease

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